Therapeutic erythromycin ester compositions



3,013,942 THERAPEUTEC ERYTHRQMYCIN ESTER CGWOSITIONS Walter H). Celmer, Garden City, N.Y., assignor, by V This invention relates to therapeutic erythromycin ester compositions and to a method of treating infections therewith. More particularly, it is concerned with therapeutic compositions containing monoacyl esters of erythromycin, wherein the acyl moiety is derived from a lower aliphatic hydrocarbon monocarboxylic acid having from two to three carbon atoms.

The present application is a continuation-in-part of the earlier filed copending U.S. patent applications Ser. No. 752,172, filed on July 31, 1958, and Ser. No. 676,366, filed on August 5, 1957, both now abandoned. Erythromycin is a well-known antibiotic which can be isolated from culture fermentation broths of Streptomyces erythraeus, a microorganism which was first isolated from a sample of Philippine soil. The complete chemical struc tures of erythromycin and erythromycin B have recently been elucidated by P. F. Wiley et *al, as described in the Journal of the American Chemical Society, vol. 79, pages 6062-6074 (1957). The erythromycin antibiotics are active against Gram-positive bacteria, but they are also effective against a few Gram-negative bacteria, such as H aemophilus influcnzae, in addition to being active against certain penicillin-resistant strains of bacteria, as well as against some large viruses; moreover, certain pathogenic protozoa have been found to be sensitive to erythromycin antibiotics.

It has customarily been the practice to administer the erythromycin antibiotics in prolected form, e.g., as entericcoated tablets, so as to avoid the aforementioned disadvantage of instability after oral administration. However, such enteric coatings, which generally consist of a cellulose acetate ester, are not applicable to finely divided substances that are to be administered in the form of aqueous suspensions, syrups, elixirs, and the like. Hence, the use of such pharmaceutical carriers with the erythromycins has not been completely satisfactory in the past. It would be desirable to obtain tasteless preparations having greater stability towards acids and which give more satisfactory blood levels when administered orally; this would be especially valuable for the administration of aqueous suspensions of the antibiotics in pediatric use to small children.

Accordingly, a primary object of the present invention is to provide a new series of pharmaceutical compositions containing certain esters of the erythromycin antibiotics which afford increased therapeutic serum levels of antibiotic activity after oral administration as compared to those levels afforded by the parent compounds or their acid addition salts. A further and more particular object of this invention is to provide novel therapeutic compositions containing the 1-mono-acety1 and propionyl ester derivatives of erythromycin antibiotics which exhibit a marked stability in aqueous media so that they afford surprisingly effective unit dosage forms for oral administration. A still further and more particular object of this invention is to provide therapeutically useful compositions comprising these active esters of the erythromycin antibiotics as medicaments together with diluent amounts of pharmaceutically acceptable, orally administrable carriers. Other objects and advantages of the invention will be apparent to those skilled in the art during the course of the descriptive part of this specification.

ttes Patent In accordance with the present invention, the foregoing objects are accomplished by the development of a new series of therapeutic compositions containing as essential active ingredients at least one compound selected from the group consisting of l-monoacylerythromycin and 1-monoacylerythromycin B, wherein said acyl groups have from two to three carbon atoms. Such compounds include l-monoacetylerythromycin, l-monoacetylerythromycin B, l-monopropionylerythromycin and l-monopropionylerythromycin B. In particular, it has been found that the advantages possessed by these particular erythromycin acyl ester-containing compositions are-manifoldz For instance, they can be more stable, having a low solubility in aqueous vehicles and a high solubility in gastric juice; they are relatively non-toxic; they are readily absorbed into the blood stream, thereby affording surprisingly rapid and significantly high therapeutic serum levels which are sustained for a relatively long period of time; and finally, they are excreted from the urine to a markedly high degree. It has also been noted that, most unlike prior art erythromycin antibiotic dosage forms, the compositions of this invention provide high blood levels of not only the erythromycin base, but also of the particular erythromycin ester component per se. Hence, the herein described therapeutic acyl ester compositions of this invention are especially valuable in view of the surprising and totally unexpected properties which they possess; moreover, such compositions also exhibit utility as excellent urinary antiseptics.

It has been found that the use of at least a substantially equivalent amount in moles of a lower acyl chloride in an inert organic solvent in the presence of a basic agent is an elfective means for the introduction of an acyl substi-tuent into the desosamine moiety of erythromycin compounds that are unsubstituted in this portion of the molecule; it is to be noted that the basic agent must be present in a substantially suflicient amount to neutralize the librated hydrochloride byproduct. This reaction may be carried out at a temperature in the range of from about 0 C. to about 50 C. for from about one to about five bicarbonates and carbonates, such as magnesium oxide,

potassium hydroxide, sodium bicarbonate and magnesium carbonate, as well as organic tertiary amines such as triethylamine, dimethylaniline, pyridine, and the like.

The usual dosage of the new compositions of this invention for administration to humans, is in the range of from approximately -2000 mg. per day and preferably in about one to about four doses. However, this dosage may vary somewhat with the weight of the subject being treated. The therapeutic compositions may be capsules, tablets, syrups, emulsions, aqueous suspensions, elix-irs and other similar pharmaceutical preparations. Preferred products are hard-filled gelatin capsules containing inert fillers suchas lactose or milk sugar, tablets (desirably, not enteric coated, i.e. soluble in gast-ic acids) containing excipients such as starch, magnesium stearate, sodium citrate, polyvinylpyrrolidone, polyethylene glycol, etc., aqueous suspensions, syrups, emulsions or elixirs in orally administrable carriers containing suitable sweetening and/or flavoring agents, coloring agents, etc. In this connection, cherry-red, raspberry-flavored syrups are often employed.

This invention is further illustrated by the following examples which are not to be considered as imposing any limitations on the scope thereof.

Example I To a solution consisting of milliequivalents (in moles) of commercially avail-able erythromycin (predominantly erythromycin together with some B and C) dissolved in 50 ml. of acetone there were added 4 g. of sodium bicarbonate. The resulting suspension was then stirred under anhydrous conditions while a solution of 10 milliequivalents (in moles) of acetyl chloride dissolved in 5 ml. of acetone was slowly added during the source of one-half hour; the reaction mixture was then stirred for an additional two hours. The inorganic material was then removed by means of filtration and the resulting filter cake was washed with ml. of acetone. The combined filtrate and washings were subsequently evaporated to dryness under reduced pressure and there was obtained an 80% yield of crystalline 1-monoacetylerythromycin having the following properties; Acetyl No., 1.0; pK 6.6 (EtOHH O 1:1); exhibited red-brown color when subjected to Keller-Kiliani test; and it was found to be relatively moderate in stability with respect to reEmtion of its antibiotic activity in dilute aqueous acid.

In the same manner, when isolated erythromycin and erythromycin B were each separately subjected to the same reaction procedure, the products obtained were respectively l-monoacetylerythromycin and l-monoacetylerythromycin B, the latter compound having the following properties: Acetyl No., 1.0; pK 6.6 (EtOH-H O 1:1); exhibited red-brown color when subjected to Keller- Kiliani test. When incorporated in tablets containing the usual water-soluble excipients and fillers and not entericcoated, each was found to be high in stability with respect to retention of its antibiotic activity in dilute aqueous acid analogous to gastric acid.

These same products were also obtained when the reaction was conducted in other inert organic solvents in lieu of acetone, such as ethyl acetate, benzene, chloroform, dioxane and diethyl ether.

Example I! When the various erythromycin antibiotics were reacted with propionyl chloride in accordance with this same Example I procedure, the products obtained were the corresponding 1-monopropionylerythromycin antibiotics.

Example III A pharmaceutical composition was prepared by blending the following materials in the proportions by weight specified:

l-monoacetylerythromycin 20.0 Tapioca star h 15.0 Sodium benzoate 6:0 Magnesium stearate 2.25 Benzalkoniurn chloride 2.0

After the dry composition was thoroughly blended, tablets were prepared from the mixture. Each tablet was of such size that it contained 25 mg. of the aforesaid ester. Similarly, other effective tablets were prepared by the same procedure, simply by substituting the desired erythromycin esters.

Example IV A 50:50 mixture by weight of l-monopropionylerythromycin and lactose was prepared by blending the aforesaid components. The mixture was then thoroughly agitated so as to obtain a powdered product that was completely uniform. Hard gelatin capsules were then filled with this mixture, using a sufficient quantity of material .to furnish 250 mg. of the active essential ingredient in Example V An elixir was prepared by combining the following elements in the parts by weight specified:

Simple syrup 75.0

Citric acid 3.0 Ethanol by volume) 20.0 Soluble saccharine 0.005 RD. & C. Red No.2 0.01 Imitation wild cherry flavor 3.3

ml. portions of the above mixture were placed in small bottles and to each of these there was added a 1 g. portion of respectively the 1-m0noacety1erythromycin prepared in Example I and the 1-monopropionylerythromycin of Example 11, together with a liquid polysorbate 80. Each elixir sample was a highly effective dosage form.

What is claimed is:

1. A therapeutic composition comprising an orally administrable pharmaceutical carrier and a compound selected from the class consisting of l-monoacetylerythromycin and 1-monopropiony1erythromycin.

2. A therapeutic composition in dosage unit form particularly adapted for oral administration, comprising a gelatin capsule containing a compound selected from the class consisting of l-monoacetylerythromycin and 1-monopropionylerythromycin, there being associated with said compound an amount of excipient bland to the gastric mucosa.

3. A therapeutic composition in dosage form comprising an orally administrable liquid pharmaceutical carrier bland to the gastric mucosa, and a member of the class consisting of l-monoacetylerythromycin and I-monopropionylerythromycin.

4. A therapeutic composition in dosage unit form comprising an orally administrable pharmaceutical carrier and l-monoacetylerythromycin.

5. A therapeutic composition in dosage unit form comprising an orally administrable pharmaceutical carrier and 1-monopropionylerythromycin.

6. The method of combating an infection caused by an organism susceptible to erythromycin, which comprises orally administering to the infected subject a member of the group consisting of l-monoacetylerythromycin and 1-monopropionylerythromycin, in a total daily dose amount of about 200 mg. to about 2000 mg.

References Cited in the file of this patent UNITED STATES PATENTS Gordon Nov. 5, 1957 Stephens Oct. 21, 1958 Booth et al Dec. 2, 1958 FOREIGN PATENTS Canada Oct. 5,

OTHER REFERENCES Hochstein et al., J.A.C.S., vol. 76, No. 20, October 20, 1954, pp. 5080-5083.

Shidlovsky et al.: Antibiotics Annual, 1953-1954, Medical Encyclopedia, Inc., 1953, pp. 548-559.

Lear: Saturday Review, January 3, 1959, pp. 35-41.

Lear: Saturday Review, February 7, 1959, pp. 43-49.

Lear: Saturday Review, September 5, 1959, pp. 45-50. 

1. A THERAPEUTIC COMPOSITION COMPRISING AN ORALLY ADMINISTRABLE PHARMACEUTICAL CARRIER AND A COMPOUND SELECTED FROM THE CLASS CONSISTING OF 1-MONACTYLERTHROMYCIN AND 1-MONOPROPIONYLERYTHROMYCIN. 